Ketamine for psychotic depression: An overview of the glutamatergic system and ketamine's mechanisms associated with antidepressant and psychotomimetic effects

Background: Converging evidence indicates that glutamatergic system and glia are directly implicated in the pathophysiology of depression. Clinical studies indicate that electroacupuncture (EA) has antidepressant-like effect with low side effects for depression. However, the underlying antidepressant mechanism of acupuncture remains obscure. Methods: Chronic unpredictable mild stress (CUMS)-induced depressive rats were used to induce depressive-like behavior, and evaluated by the weight change, open field test, sucrose preference test, and novelty suppressed feeding test. EA, NMDA receptor subunit 2A antagonist (NR2A RA) or NMDA receptor subunit 2B antagonist (NR2B RA) was used for comparison. High performance liquid chromatography (HPLC) was performed to detect the content of hippocampal glutamate, while western blot for the hippocampal protein expression levels of calcium/calmodulin-dependent protein kinase II (CaMKII), Bax, caspase 3 and B-cell lymphoma-2 (Bcl-2). The distribution of glutamate ionotropic receptor NMDA type subunit 2A (NR2A), neuronal nuclear protein (NeuN), glutamate ionotropic receptor NMDA type subunit 2B (NR2B) and glial fibrillary acidic protein (GFAP) were detected by immunofluorescence. Results: Significant depression behavior (reduced body weight and sucrose preference, increased feeding and immobility time) was produced in CUMS-induced depressive rats, which was reversed significantly by EA. EA decreased hippocampal glutamate level. EA led to a significant decrease in expression levels of Bax, caspase 3 and CaMKⅡ accompanied by increased Bcl-2 expression level. Furthermore, EA significantly increased NR2A expression level as well as decreased NR2B expression level in hippocampus. Conclusion: EA ameliorated depression-like behavior in CUMS rats, which might be mediated, at least in part, by regulating the glutamate, NMDA receptors and apoptosis in the hippocampus.

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Does variation in trait schizotypy and frequency of cannabis use influence the acute subjective, cognitive and psychotomimetic effects of delta-9-tetrahydrocannabinol? A mega-analysis

Journal of Psychopharmacology ◽

10.1177/0269881120959601 ◽

2021 ◽

pp. 026988112095960

Author(s):

Abigail M Freeman ◽

Claire Mokrysz ◽

Chandni Hindocha ◽

Will Lawn ◽

Celia JA Morgan ◽

...

Keyword(s):

Personality Traits ◽

Memory Impairment ◽

Linear Models ◽

Cannabis Use ◽

Acute Effects ◽

Double Blind ◽

Schizotypal Personality ◽

Domain Specific ◽

Individual Participant ◽

Psychotomimetic Effects

Background: While the acute effects of cannabis are relatively benign for most users, some individuals experience significant adverse effects. This study aimed to identify whether variation in schizotypal personality traits and frequency of cannabis use influence the acute effects of delta-9-tetrahydrocannabinol (THC). Methods: Individual participant data from four double-blind, randomised, placebo-controlled, acute crossover studies involving 128 cannabis users were combined for a mega-analysis. Using multilevel linear models and moderation analyses, frequency of cannabis use and schizotypal personality traits were investigated as potential moderators of the subjective, cognitive and psychotomimetic effects of acute THC. Results: There was evidence of a moderating effect where increased frequency of cannabis use was associated with reduced intensity of subjective (changes in alertness and feeling stoned) and psychosis-like effects following THC when compared with placebo. Moderating effects of cannabis use frequency on acute memory impairment were weak. Trait schizotypy did not moderate the acute psychosis-like effects of THC compared with placebo. Conclusions: Our results suggest that a pattern of domain-specific tolerance develops to the acute effects of THC. Tolerance to the alertness-reducing effects occurred more readily than tolerance to psychotomimetic effects. Only partial tolerance to feeling stoned was found, and there was weak evidence for tolerance to memory impairment. Trait schizotypy did not moderate THC’s effects on psychotomimetic symptoms.

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Clinical and psychometric validation of the psychotic depression assessment scale

Journal of Affective Disorders ◽

10.1016/j.jad.2014.11.012 ◽

2015 ◽

Vol 173 ◽

pp. 261-268 ◽

Cited By ~ 17

Author(s):

Søren D. Østergaard ◽

Christina H. Pedersen ◽

Peter Uggerby ◽

Povl Munk-Jørgensen ◽

Anthony J. Rothschild ◽

...

Keyword(s):

Assessment Scale ◽

Psychometric Validation ◽

Psychotic Depression ◽

Depression Assessment

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Aerobic Exercise Prevents Depression via Alleviating Hippocampus Injury in Chronic Stressed Depression Rats

Brain Sciences ◽

10.3390/brainsci11010009 ◽

2020 ◽

Vol 11 (1) ◽

pp. 9

Author(s):

Jie Kang ◽

Di Wang ◽

Yongchang Duan ◽

Lin Zhai ◽

Lin Shi ◽

...

Keyword(s):

Aerobic Exercise ◽

Mild Stress ◽

Glutamatergic System ◽

Sprague Dawley ◽

Bdnf Expression ◽

Sprague Dawley Rats ◽

Immobility Time ◽

Neurotoxic Effects ◽

Swimming Test ◽

Underlying Mechanisms

(1) Background: Depression is one of the overwhelming public health problems. Alleviating hippocampus injury may prevent depression development. Herein, we established the chronic unpredictable mild stress (CUMS) model and aimed to investigate whether aerobic exercise (AE) could alleviate CUMS induced depression-like behaviors and hippocampus injury. (2) Methods: Forty-eight healthy male Sprague-Dawley rats (200 ± 20 g) were randomly divided into 4 groups (control, CUMS, CUMS + 7 days AE, CUMS + 14 days AE). Rats with AE treatments were subjected to 45 min treadmill per day. (3) Results: AE intervention significantly improved CUMS-induced depressive behaviors, e.g., running square numbers and immobility time assessed by the open field and forced swimming test, suppressed hippocampal neuron apoptosis, reduced levels of phosphorylation of NMDA receptor and homocysteine in hippocampus, as well as serum glucocorticoids, compared to the CUMS rats. In contrast, AE upregulated phosphorylation of AMPAR receptor and brain-derived neurotrophic factor (BDNF) hippocampus in CUMS depression rats. The 14 day-AE treatment exhibited better performance than 7 day-AE on the improvement of the hippocampal function. (4) Conclusion: AE might be an efficient strategy for prevention of CUMS-induced depression via ameliorating hippocampus functions. Underlying mechanisms may be related with glutamatergic system, the neurotoxic effects of homocysteine, and/or influences in glucocorticoids-BDNF expression interaction.

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Cannabinoids, reward processing, and psychosis

Psychopharmacology ◽

10.1007/s00213-021-05801-2 ◽

2021 ◽

Author(s):

Brandon Gunasekera ◽

Kelly Diederen ◽

Sagnik Bhattacharyya

Keyword(s):

Psychotic Disorders ◽

Neural Substrates ◽

Brain Regions ◽

Reward Processing ◽

Anterior Cingulate ◽

Psychotic Symptoms ◽

Dopamine Synthesis ◽

Future Research ◽

Drug Challenge ◽

Psychotomimetic Effects

Abstract Background Evidence suggests that an overlap exists between the neurobiology of psychotic disorders and the effects of cannabinoids on neurocognitive and neurochemical substrates involved in reward processing. Aims We investigate whether the psychotomimetic effects of delta-9-tetrahydrocannabinol (THC) and the antipsychotic potential of cannabidiol (CBD) are underpinned by their effects on the reward system and dopamine. Methods This narrative review focuses on the overlap between altered dopamine signalling and reward processing induced by cannabinoids, pre-clinically and in humans. A systematic search was conducted of acute cannabinoid drug-challenge studies using neuroimaging in healthy subjects and those with psychosis Results There is evidence of increased striatal presynaptic dopamine synthesis and release in psychosis, as well as abnormal engagement of the striatum during reward processing. Although, acute THC challenges have elicited a modest effect on striatal dopamine, cannabis users generally indicate impaired presynaptic dopaminergic function. Functional MRI studies have identified that a single dose of THC may modulate regions involved in reward and salience processing such as the striatum, midbrain, insular, and anterior cingulate, with some effects correlating with the severity of THC-induced psychotic symptoms. CBD may modulate brain regions involved in reward/salience processing in an opposite direction to that of THC. Conclusions There is evidence to suggest modulation of reward processing and its neural substrates by THC and CBD. Whether such effects underlie the psychotomimetic/antipsychotic effects of these cannabinoids remains unclear. Future research should address these unanswered questions to understand the relationship between endocannabinoid dysfunction, reward processing abnormalities, and psychosis.

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Association between psychomotor disturbance and treatment outcome in psychotic depression: a STOP-PD II report

Psychological Medicine ◽

10.1017/s0033291721000805 ◽

2021 ◽

pp. 1-7

Author(s):

Alastair J. Flint ◽

Kathleen S. Bingham ◽

Nicholas H. Neufeld ◽

George S. Alexopoulos ◽

Benoit H. Mulsant ◽

...

Keyword(s):

Treatment Outcome ◽

Acute Phase ◽

Controlled Trial ◽

Future Research ◽

Psychotic Depression ◽

Regression Analyses ◽

Open Label ◽

Randomized Controlled ◽

Stabilization Phase ◽

The Relationship

Abstract Background Little is known about the relationship between psychomotor disturbance (PMD) and treatment outcome of psychotic depression. This study examined the association between PMD and subsequent remission and relapse of treated psychotic depression. Methods Two hundred and sixty-nine men and women aged 18–85 years with an episode of psychotic depression were treated with open-label sertraline plus olanzapine for up to 12 weeks. Participants who remained in remission or near-remission following an 8-week stabilization phase were eligible to participate in a 36-week randomized controlled trial (RCT) that compared the efficacy and tolerability of sertraline plus olanzapine (n = 64) with sertraline plus placebo (n = 62). PMD was measured with the psychiatrist-rated sign-based CORE at acute phase baseline and at RCT baseline. Spearman's correlations and logistic regression analyses were used to analyze the association between CORE total score at acute phase baseline and remission/near-remission and CORE total score at RCT baseline and relapse. Results Higher CORE total score at acute phase baseline was associated with lower frequency of remission/near-remission. Higher CORE total score at RCT baseline was associated with higher frequency of relapse, in the RCT sample as a whole, as well as in each of the two randomized groups. Conclusions PMD is associated with poorer outcome of psychotic depression treated with sertraline plus olanzapine. Future research needs to examine the neurobiology of PMD in psychotic depression in relation to treatment outcome.

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